Molecular Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
J Immunol. 2024 Apr 15;212(8):1366-1380. doi: 10.4049/jimmunol.2300839.
mAbs to MHC class I (MHC-I) molecules have proved to be crucial reagents for tissue typing and fundamental studies of immune recognition. To augment our understanding of epitopic sites seen by a set of anti-MHC-I mAb, we determined X-ray crystal structures of four complexes of anti-MHC-I Fabs bound to peptide/MHC-I/β2-microglobulin (pMHC-I). An anti-H2-Dd mAb, two anti-MHC-I α3 domain mAbs, and an anti-β2-microglobulin mAb bind pMHC-I at sites consistent with earlier mutational and functional experiments, and the structures explain allelomorph specificity. Comparison of the experimentally determined structures with computationally derived models using AlphaFold Multimer showed that although predictions of the individual pMHC-I heterodimers were quite acceptable, the computational models failed to properly identify the docking sites of the mAb on pMHC-I. The experimental and predicted structures provide insight into strengths and weaknesses of purely computational approaches and suggest areas that merit additional attention.
单克隆抗体（mAbs）针对 MHC Ⅰ类（MHC-I）分子已被证明是组织分型和免疫识别基础研究的重要试剂。为了增强我们对一组抗 MHC-I mAb 所识别表位的理解，我们确定了与肽/MHC-I/β2-微球蛋白（pMHC-I）结合的四种抗 MHC-I Fabs 复合物的 X 射线晶体结构。一种抗 H2-Dd mAb、两种抗 MHC-I α3 结构域 mAb 和一种抗 β2-微球蛋白 mAb 在与先前的突变和功能实验一致的部位结合 pMHC-I，结构解释了等位基因特异性。将实验确定的结构与使用 AlphaFold Multimer 计算得出的模型进行比较表明，尽管对单个 pMHC-I 异二聚体的预测相当不错，但计算模型未能正确识别 mAb 在 pMHC-I 上的对接部位。实验和预测的结构深入了解了纯计算方法的优缺点，并提出了值得进一步关注的领域。
